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Exciting developments in TB diagnosis, prevention, and
treatment
Amita Gupta MD MHSAssociate Professor of Medicine and International Health
Center for Clinical Global Health Education
Johns Hopkins University [email protected]
XI HIV/AIDS Johns Hopkins/Brazil Conference, April 19, 2013
Overview
• Epidemiology
• Novel diagnostics
• Management
– When to start ART
– Drug interactions
– TB-associated IRIS
– Drug resistant TB
• Prevention of TB
– INH, ART
– Novel regimens
– Vaccines
Disclosures
• I receive funding from the
– US National Institutes of Health
– Indian Department of Biotechnology and Indian Council of Medical Research
– Gilead Foundation
– Ujala Foundation
– World Health Organization
• Any opinions expressed are my own and not of any of my sponsors.
Epidemiology
Trends in Estimated TB incidence rates overall (green) and among HIV-positive (red), selected
high-burden countries, 1990–2010
Global TB Control, WHO Report 2011
Brazil TB snapshot
• In 2011, 74892 cases reported
• 71337 new and 10045 retreatment
– 40294 smear +
– 12683 smear -
– 8278 unknown
– 10017 extrapulmonary
– 2450 among <15 year olds
– 566 MDR TB
• Financing $86 million USD, 91% domestic source
74%69%46%
Global TB Control, WHO Report 2012
HIV testing, treatment for HIV-positive TB patients and prevention of TB among people
living with HIV in BRICS countries
HIV+/TB incidence
rate/100,000
TB pts with
known HIV*
% of TB pts tested
for HIV
% HIV+
%
started on CPT
% started on ART
No. screen
ed for TB*
No. on IPT*
Brazil 16 49 58 20 - 80 - -
Russia 9 79 - - - - - -
India 94 689 45 9 91 59 386 -
China 13 209 23 2 - 36 - -
South Africa
330 323 83 65 76 44 1256 373
Global TB Control, WHO Report 2012
*Number are in thousands
TB Diagnosis
TB Diagnosis
• Only 65% of TB cases diagnosed and treated globally
• <5% cases tested for MDR
• Diagnostic delays increase mortality
New Diagnostics
LED microscopy
Line probe assays
Urine Lam Dipstick
Boehme CC et al. N Engl J Med2010;363:1005-1015
Sensitivity 68-98% Specificity 99-100%
Proportion of results reported to clinics from time of sputum collection
Time to treatment
Smear-,cx+ 56 days vs 5 days
Median time to
detection
0 days MTB/RIF
1 day smear
16 days liquid cx
30 days solid cx
DST-RIF Resistance
1 day MTB/RIF
20 days LPA
106 days standard
phenotyping
Boehme Lancet 2011
Lawn & Zumla, Exp Rev Anti-Infect Ther 2012
452 children
• <15 years old
• 24% HIV+
• 6% AFB smear+
• 16% Cx+
• 13% MTB/RIF+
• MTB/RIF detected twice as many TB cases compared to smear 76% vs 38%
(all smear+ and 61% of smear-)
– Testing a second sputum in smear (-) cases increased sensitivity by 28%
– Specificity 99%
– Median 1 day vs 12 days for cx
Lancet ID 2011
Determine TB Urine Lipoarabinomannan (LAM) Antigen detection
• ELISA
• Newer Lateral flow point of care assay (like a pregnancy test)
• LAM -17.5kd glycolipid protein in MTB cell wall released from active or degrading MTB cells in urine
Neg Intermed+ Strong+
Urine LAM
• Overall sensitivity: 50%
• Specificity: 50-100%
• Urinary excretion of LAM correlates with MTB burden and hence shows prognosis
• Cross reactivity with Candida spp and normal oral flora containing LAM-like molecules
• Poor sensitivity and specificity in pleural, pericardial, CSF
Dheda et al, 2013
Urine TB LAM detection in HIV+ depends on CD4 count
Dheda PLOS 2010; Shah JAIDS 2009; Lawn AIDS 2009; Lawn Lancet ID 2011; Minion Eur Resp J 2011
Sensitivity highest in HIV+ with
advanced immunosuppression
Among 101 culture confirmed TB patients with median CD4 60, Uganda
Shah et al, CROI 2013
“Niche clinical utility” rapid TB screening tool for HIV+ with low CD4, starting ART in high TB/HIV burden settings
TB diagnosis in children
• Further diagnostic studies needed
– Xpert in different TB/HIV settings, extrapulmonary TB
– LAM being evaluated but appears to be low yield
– String test, stool test being evaluated
• Consensus statements for evaluation of TB diagnostics in children
– Graham JID 2012; Cuevas JID 2012
TB Treatment
WHO/photographer Jean Chung http://stoptb.org/resources/photos/
When to treat TB
in setting of ART?
Initiation of ART during vs. after TB
treatment: SAPIT
Abdool Karim S (2010) NEJM 362: 697.
Significant survival benefit to providing ART during TB treatment rather than waiting until completion of TB treatment
Key characteristics of trials of timing
of ART during TB treatment
Study Setting ART start
Key
enrollment criteria
Median CD4 (IQR)
Primary endpoint
CAMELIA(Blanc, ANRS)
Cambodia2 wks vs.
8 wks
Smear +, CD4 < 200
25 (10 - 56)
Death
STRIDE(Havlir, ACTG)
Multi-national
2 wks vs.
8-12 wks
Clinical TB, CD4 < 250
77 (36 – 145)
AIDS or death
SAPIT(Abdool-Karim,
CAPRISA)
South Africa
1st 4 wks vs.
8-12 wks
Smear +, CD4 < 500
150 (77 – 254)
AIDS or death
AIDS 2010 abstract THLBB106, CROI 2011 abstract 38, CROI 2011 abstract 39LB
Abdool Karim NEJM 2010; Blanc NEJM 2011; Havlir NEJM 2011
For patients who get TB, early ART reduces
death (CAMELIA) or death/AIDS (STRIDE, SAPIT)
34% ↓p=0.004
19% ↓
p=0.45
11% ↓
p=0.7334% ↓
p=0.004
42% ↓
p=0.02
68% ↓
p=0.06
CD4 < 50Overall
Abdool Karim NEJM 2010; Blanc NEJM 2011; Havlir NEJM 2011
Viral suppression – no effect of timing of ART on suppression at end of TB treatment
ART switches – higher in immediate arm of SAPIT
Risk of IRIS with ART during TB treatment
A5221/ STRIDE3 CAMELIA1 SAPIT Integrated2
N 806 660 429
CD4+ (IQR) 77 (36,145) 25 (11,56) 150 (77, 254)
IRIS 8% 25% 14%
Earlier vs.
later ART10% vs. 5%
33% vs.14%
(p<0.05)
20% vs. 8%
(p<0.001)
Severe IRIS,
earlier vs.
later ART
3% (13/405) vs. 2%(6/401),
No IRIS deaths
Severity data not
available,
7 deaths(6 immediate)
7%(15/214) vs 2%(4/215),
2 deaths (immediate)
1 Laureillard IAS 2011 WEAX0104, Blanc NEJM 2011,
2 Naidoo IAS 2011 WEAX01051, Karim NEJM 2011
3 Luetkemeyer, CROI 2012, Havlir NEJM 2011
Timing of ART in patients with TB
• Advanced AIDS (CD4 < 50): immediate ART (within 2 weeks) improves survival
– Increased risk IRIS, including fatal IRIS
– Overall survival benefit despite this
• CD4 > 50: early ART (~ 2 months) provides good balance of competing risks of death/AIDS vs. IRIS
• Caveats
– CNS involvement – no benefit to immediate therapy, and there may be increased risk* (Torok, CID, 2011)
Which drugs to use?
Nucleus
Cyt
opla
sm
PXR
RXR
RIF
RIF PXR RXR
CYP3A4proximalpromoter
Phase II enzyme
regulatory genes
PGPregulatory
gene
MDR1 proteinregulatory
gene
DNA
mRNA
CYP 3A4XRE
Dooley (2008) JID 198: 948.
RIFAMPIN: A promiscuous inducer of metabolizing enzymes
Important Drug Interactions with
Rifampin• NRTIs (AZT, 3TC, TDF, etc.)
– No significant interactions
• NNRTIs (EFV, NVP, rilpivirine, etravirine)
– RIF decreases NVP exposure 40-50%,
– EFV decreases 20-35% but effects highly variable. In some levels of EFV actually increased (TT genotype)
– RIF decreases rilpivirine 80%-> do not coadminister
– RIF decreases etravirine->do not coadminister
• Protease inhibitors (LPV/r, DRV/r, ATV/r, etc.)
– RIF decreases exposure >80%, in most cases
– Increasing the PI dose can lead to hepatotoxicity
• CCR5 Inhibitors (Maraviroc)
– RIF reduces maraviroc exposure by 63%
• Integrase inhibitors (RAL)
– RIF reduces raltegravir exposure by 40-60%Slide Courtesy of Kelly Dooley, JHU
Antiretroviral Interactions Rifampin
All PIs PIs � >75% NOT RECOMMENDED
(DOUBLE DOSE of PIs being
studied but toxicities a concern)
All NRTIs No significant interactions No dose change
NNRTIs
EFV EFV � 26%
CYP2B6 TT genotype �EFV
(more common in Blacks/
African and Indians)
EFV 600mg once daily
(FDA recommends 800mg
for>50kg but no clinical evidence
to support the need for this)
NVP � 20%-58%
ETR Significant � DO NOT USE
RPV RPV AUC� 80% DO NOT USE
Integrase inhibitors
RAL RAL AUC � 40%, cmin 61% 800mg BID*
EVG/COB/TDF/FTC Significant � expected DO NOT USE
MVC AUC � 64% Not recommended but if
necessary 600mg BID if no CYP3a
inhibitor present
Raltegravir + rifampin
Wenning (2009) AAC 53: 2852.
Virologic suppression with RAL
800 once-daily vs. 400 mg twice-daily (HIV patients without TB)
RAL 400 mg twice-daily alone
RAL 800 mg twice-daily with RIF
Eron, CROI 2011, Abstract # 150LB
Recommendation: Raltegravir at a dose of 800 mg twice daily with rifampin is an acceptable alternative. Employ with caution, though, because clinical significance of lower troughs is unknown
Slide Courtesy of Kelly Dooley, JHU
Efavirenz vs Raltegravir for HIV/TB: REFLATE Phase II Trial
• 153 HIV/TB pts (most Brazilian)
• 3 arms
• EFV 600mg QD
• RAL 400mg BID
• RAL 800mg BID
Proportion with VL<50 at 48 weeks: 73% EFV vs 75% RAL 400 vs 65% RAL 800
Grinsztejn et al Poster 853, CROI 2013
Lopinavir/ritonavir + rifampin
Day 0: LPV/r at a dose of 400/100 twice daily alone
Day 21: LPV/r at a dose of 800/200 twice daily together with rifampin
Day 15: LPV/r at a dose of 600/150 twice daily together with rifampin
Recommendation:For patients already taking LPV/r who require RIF, gradual increase in LPV/r dose to double the dose may be effective.
Decloedt (2011) AAC 55: 3195.Slide Courtesy of Kelly Dooley, JHU
Antiretrovirals and RifabutinARV Interaction/ PK
effect
Rifabutin Recommended dose
PIs
ATV/r Rifabutin 150mg once daily
OR
300mg three times a week.
Monitor for antimycobacterial
activity and consider TDM
DRV/r
FPV/r
LPV/r
SQV/r
TPV/r
NRTIs
AZT
TDF
d4T
ABC
No interaction No dose change
5mg/kg daily (max dose 300mg
once daily)
Rifabutin + Boosted PIs – some issues
• Bidirectional drug interactions– RBT is metabolized by cytochrome P450 (CYP) 3A4, so you
have to decrease the dose when you give it with CYP3A4 inhibitors, like ritonavir, to avoid toxicities
• Expensive, not widely available
• Efficacy data is scanty– Clinical trials comparing RBT to RIF were largely conducted
among patients not taking ARVs
– Reports of rifamycin resistance in patients receiving 150mg every other day (Jenny-Avital et al, CID 2009)
HKCS/BMRC 1992; Gonzalez-Montaner 1994; McGregor 1996; Rowinska-Zakrzowska 1992; Schwander 1995
We don’t know what dose of RBT to give when RBT is given together with a PI.
Boosted PI + rifabutin
Among 16 patients receiving rifabutin plus LPV/r:•6 with Grade 3 hepatitis•3 with Grade 3 neutropenia•1 with Grade 2 uveitis
Recommendation:Boosted lopinavir together with rifabutin is an option. Dosing RBT at 150 mg daily is likely necessary to achieve therapeutic concentrations
Caveats:•Monitor for hepatotoxicity and neutropenia•If you stop the ARVs, make sure to adjust the RBT dose back to 300 mg daily
Naiker, CROI 2011, abstract 650. Slide Courtesy of Kelly Dooley, JHU
Antiretroviral Interaction/PK effect RIFABUTIN
Integrase inhibitors
RAL NO DOSE CHANGE
EVG/COB/TDF/FTC DO NOT USE
NNRTIs
EFV RFB AUC � 38% Rifabutin 450-600mg once
daily or 600mg 3 times/wk
NVP RFB AUC� 17% No dose change
ETR RFB and metabolite � 17%
ETR AUC � 37%
If ETR with PI/r->DO NOT USE
300mg once daily if no PI
RPV RPV AUC �46% DO NOT USE
Other
MVC MVC �possible If strong CYP3A inducer , MVC
300mg BID
If strong CYP3A inhibitor
MVC 150mg BID
T20 No interaction No dose change
Overlapping toxicities
Adverse Reaction TB Drugs HIV Drugs
Rash PZA, RIF, INH NNRTIs, ABC,
T/S
Hepatotoxicity INH, RIF, PZA PIs, NVP
Nausea RIF, PZA, INH RTV, AZT,
APV
Cytopenias RBT, RIF AZT, T/S
CNS INH EFVNot to mention pill burden and coordination of services…..
Slide Courtesy of Kelly Dooley, JHU
Available guidance
http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/PDF/tbhiv.pdf
http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf
What are the co-treatment options?
• Efavirenz-based ART with rifampin-containing
TB treatment -preferred
• Nevirapine + rifampin- alternative• NVP should be given at 200 mg twice daily
throughout co-treatment
• Raltegravir + rifampin
• Super-boosted lopinavir or double-dose
lopinavir/ritonavir + rifampin
• Protease inhibitor + rifabutin
• Triple/quadruple NRTI + rifampin
Slide Courtesy of Kelly Dooley, JHU
NC002 Phase II PA-824, moxifloxacin, PZA novel combination for both Drug Sensitive TB and MDR TBNC003 PA-824, TMC207, PZA and clofazimine
MDR TB
• Pulmonary MDR TB: Phase IIb TMC207
(bedaqualline) Diacon NEJM 2009; IUATLD 2010 Berlin
– 13% HIV+ of 47 patients
– At 8 weeks, addition to TMC207 to OBR increased sputum culture
conversion from 9% to 48%
– At 24 weeks (8 weeks of TMC207 +OBR then standard treatment vs
standard treatment) 58% vs 79%
• 9 month Bangladesh regimen Van Deun Am J Resp Crit Care
Med 2010
– Observational study of 206 patients (almost all HIV-negative)
– No prior second-line TB treatment
– 9 months of Gatifloxacin, clofazamine, ethambutol, PZA with 4 month
intensive phase of prothionamide, kanamycin, high dose INH
– Relapse-free cure 88%
– Infrequent and manageable AEs
14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide,
and moxifloxacin combinations: a randomised trial Andreas H Diacon MD a d , Rodney Dawson MD e, Florian von Groote-Bidlingmaier MD d, Gregory Symons
MBChB e, Amour Venter NatDipTech b, Prof Peter R Donald MD c, Christo van Niekerk MD g, Daniel Everitt MD f, Helen Winter PhD h, Piet Becker PhD i, Carl M Mendel MD f, Melvin K Spigelman MD f
The Lancet Volume 380, Issue 9846, Pages 986 - 993, September 2012
Linezolid for Treatment of Chronic Extensively Drug-Resistant TuberculosisMyungsun Lee, M.D., Jongseok Lee, Ph.D., Matthew W. Carroll, M.D., Hongjo Choi, M.D., Seonyeong Min, R.N., Taeksun Song, Ph.D., Laura E. Via, Ph.D., Lisa C. Goldfeder, C.C.R.P., Eunhwa Kang, M.Sc., Boyoung Jin, R.N., Hyeeun Park, R.N., Hyunkyung Kwak, B.S., Hyunchul Kim, Ph.D., Han-Seung Jeon, M.S., Ina Jeong, M.D., Joon Sung Joh, M.D., Ray Y. Chen, M.D., Kenneth N. Olivier, M.D., Pamela A. Shaw, Ph.D., Dean Follmann, Ph.D., Sun Dae Song, M.D., Ph.D., Jong-Koo Lee, M.D., Dukhyoung Lee, M.D., Cheon Tae Kim, M.D., Veronique Dartois, Ph.D., Seung-Kyu Park, M.D., Sang-Nae Cho, D.V.M., Ph.D., and Clifton E. Barry, III, Ph.D.
N Engl J Med; 367:1508-1518, October 2012
TB Prevention
Treatment as Prevention: The
case for (latent) TB
IPT
HAART
HAART +IPT
Newer regimens
Isoniazid Preventive Therapy (IPT)
Reduces Risk of TB among PLHIV
Akolo 2010 Cochrane review
HIV+, TST+ received 6 months IPT in Rio de Janeiro (THRio study)2135 pts, 1615 began IPT, 42 developed TB (IR 0.51/100PY)50% of TB occurred within 12 mo of IPT stopping (almost all among non-completers)
TB incidence: Completed IPT 0.51/100PYIncomplete IPT 1.03/100PYNever had IPT 6.74/100PY
Conclusion: 6 months of IPT may be durable for Brazil
Golub
Number
of Cases
ART reduction in TB risk by baseline CD4 group
Overall (any CD4)65% reduction
CD4 0-19984% reduction
CD4 200-35066% reduction
CD4 >35057% reduction
Suther et al PLOS Med 2012
Combined ART and IPT appears to provide
greater reduction in TB risk
Rangaka AIDS 2012
New WHO IPT Guidelines for HIV+ in high
HIV/TB regions (December 2010)
5/8/2013 57
New WHO TB symptom screening
tool for HIV-infected
• Any current cough, fever, night sweats, or
weight loss
• Meta-analysis of 12 studies
– Sensitivity: 90% in clinical settings
– Negative predictive value: 97.7% and 90% in 5%
and 20% TB prevalence among HIV respectively
– Minimal incremental value of chest Xray
Getahun PLOS Med 2011, WHO Guidance December 2010; Gupta CID 2011
3mo High dose INH/Rifapentine given
weekly is non-inferior to 9 mo INH
900mg INH/900mg RPT weekly for 12 wks
Weekly High Dose 3HP vs 9H in HIV+ not on ART (N=393)
• Enrollment of HIV+ ongoing to assess tolerability
• In MITT analysis, persons receiving 3 HP
– Had higher completion rates (89% vs 65%,p=0.04)
– Fewer AEs (22 vs 40, p=0.004)
– Less hepatotoxicity (2% vs 6%, p=0.03)
• PK studies ongoing to assess RFP and EFV interactions
Sterling AIDS 2012, IAS MOA B0302
Summary TB prevention in HIV+ adults
• IPT, HAART and HAART+IPT all reduce TB
– Adherence important
– More benefit of IPT in TST+
• 6 month INH in HIV+ TST+ appears to offer durable
protection in Brazil setting
• 3RPT/INH: a new safe and effective alternative that
appears potentially superior to 9INH
• Regimen not yet recommended for HIV patients on ART as PK data not available
• Simple TB screen: absence of fever, night sweats, cough, weight loss (with or without CXR) can be used to initiate TB preventive regimen
• ACTG 5279: Phase III trial assessing ultra-short LTBI treatement with daily INH/rifapentine x 4weeks in
What about TB prevention in HIV-infected and
HIV-exposed children?
Conflicting Data on IPT in Children
CHER Study Showed ART Benefit in
Preventing TB in Children
Summary guidance for children• Brazil guidelines
– Contact tracing and IPT are priorities
– Positive TST≥5mm in >2 yrs old BCG vaccinated
children; or non-BCG children or
immunosuppressed ( e.g. HIV+)
– ART to HIV+ children
– TST≥10mm in <2 yrs old BCG vaccinated
• WHO and Brazil guidance
– INH to TB-exposed children <5 years and to HIV-
infected children remains critical
• INH/rifapentine PK and efficacy to be studied
further
The development pipeline for new
TB vaccines, 2012
MV85A/AERAS-485 Phase II RCT in infantsWell tolerated but no efficacyTameris et al , Lancet March 23, 2013
Combination Prevention
WHO Health Organization
Conclusions• TB incidence, prevalence, mortality declining
• Several novel rapid TB diagnostics for TB
– Xpert
– Xpert + LAM in low CD4 group
– Cost-effective
• Need better rates of testing TB patients for
HIV but Brazil doing a great job with ART
• Further Implementation of TB screening and
IPT scale-up needed
• Novel shorter courses for LTBI being studied in
HIV-infected persons on ART
•
Conclusions
• “Co-treatment” – both infections must be treated
• Much progress on timing of ART initiation
– CD4 < 50: immediate (2 weeks)
– CD4 > 50: early (2-3 months)
• Several co-treatment options, but more data needed
– New guidance for daily rifabutin dosing with PI
– RAL and Rifampin appear to be an option
– Guidelines available, Research in progress
• Several new drugs in clinical development for
prevention and treatment of drug sensitive and MDR
TB, so new options are on their way
AcknowledgementsConference organizers
Adriana Andrade, Joel Gallant, Beatriz Grinsztejn, Esaú
Custódio João Filho, Mauro Schechter, Valdiléa G. Veloso,
Claudia Antonaccio
Some slides adapted from Lisa Nelson WHO STOP TB, Kelly
Dooley JHU, Jonathan Golub JHU
EFV + Rifampin – preferred option
Recommendation: Use EFV and rifampin together without dose adjustment of EFV
Boulle (2008) JAMA 5: 530Manosuthi (2009) CID 48: 1752
NVP + rifampin: alternative optionP
rop
ort
ion
with
de
tecta
ble
vir
al lo
ad
Months on ART
TB patients here were on TB treatment then started ART
Patients here were on stable ART and then developed TB
and started TB drugs
TB+HIV
HIV only
Recommendation: If EFV cannot be used, NVP and rifampin is an acceptable alternative. NVP should be given at 200 mg twice daily throughout co-treatment
Boulle (2008) JAMA 5: 530
Bonnet, abstract WELBX05, IAS Rome,